Classifications

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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This invention relates to novel hydroxamic acid derivatives that are useful for the treatment of bacterial infections, especially Gram-negative infections.
• the invention also relates to methods of using such compounds in the treatment of bacterial infections in mammals, and to pharmaceutical compositions containing such compounds.
• Gram-negative bacteria are unique in that their outer membrane contains lipopolysaccharide (LPS), which is crucial for maintaining membrane integrity, and is essential for bacterial viability (reviewed in Ann. Rev. Biochem 76: 295-329, 2007).
• LPS lipopolysaccharide
• the major lipid component of LPS is Lipid A, and inhibition of Lipid A biosynthesis is lethal to bacteria.
• Lipid A is synthesized on the cytoplasmic surface of the bacterial inner membrane via a pathway that consists of nine different enzymes. These enzymes are highly conserved in most gram-negative bacteria.
• LpxC is the enzyme that catalyzes the first committed step in the Lipid A biosynthetic pathway, the removal of the N-acetyl group of UDP-3-O—(R-3-hydroxymyristoyl)-N-acetylglucosamine.
• LpxC is a Zn 2+ -dependent enzyme that has no mammalian homologue, making it a good target for the development of novel antibiotics.
• Several inhibitors of LpxC [UDP-3-O—(R-3-hydroxymyristoyl)-GlcNAc deacetylase] with low nM affinity have been reported (Biochemistry 45: 7940-48, 2006).
• LpxC inhibitors A new class of LpxC inhibitors has been discovered. These compounds, or their pharmaceutical salts, can be represented by Formula I below:
• R 1 is represented by C 1 -C 3 alkyl
• R 2 is represented by hydrogen or C 1 -C 3 alkyl
• R 3 is represented by hydrogen, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, or trifluoromethoxy
• L is absent, or is represented by a moiety selected from the group consisting of C 1 -C 6 alkylene which may be optionally substituted, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene, —(CH 2 ) p —O—(CH 2 ) n , —(CH 2 ) p —O—(CH 2 ) z —O—(CH 2 ) n —; n is represented by an integer ranging from 0 to 4; p is represented by an integer ranging from 0 to 4; q is represented by an integer ranging from 0 to 6; z is represented by an integer ranging from 1 to 4;
• the compounds of Formula I exhibit antibacterial activity, especially against Gram-negative organisms. They may be used to treat bacterial infections in mammals, especially humans. The compounds may also be used for veterinary applications, such as treating infections in livestock and companion animals.
• the compounds of Formula I are useful for treating a variety of infections; especially Gram-negative infections including nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intraabdominal infections, lung infections (including those in patients with cystic fibrosis), Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.), endocarditis, diabetic foot infections, osteomyelitis, and central nervous system infections.
• Gram-negative infections including nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intraabdominal infections, lung infections (including those in patients with cystic fibrosis), Helicobacter pylori (and relief of associated gastric complications such as peptic ulcer disease, gastric carcinogenesis, etc.), endocarditis, diabetic foot infections, osteomyelitis, and central nervous system infections.
• the compounds will typically be admixed with at least one excipient and formulated into a pharmaceutical dosage form.
• dosage forms include tablets, capsules, solutions/suspensions for injection, aerosols for inhalation and solutions/suspensions for oral ingestion.
• phrases “pharmaceutically acceptable salt(s)”, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention.
• the compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
• the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salt
• the invention also relates to base addition salts of the compounds of the invention.
• the chemical bases that may be used as reagents to prepare these pharmaceutically acceptable base salts are those that form non-toxic base salts with such compounds.
• Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
• Suitable base salts are formed from bases which form non-toxic salts.
• suitable base salts include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
• Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
• Certain of the compounds of the formula (I) may exist as geometric isomers.
• the compounds of the formula (I) may possess one or more asymmetric centers, thus existing as two, or more, stereoisomeric forms.
• the present invention includes all the individual stereoisomers and geometric isomers of the compounds of formula (I) and mixtures thereof. Individual enantiomers can be obtained by chiral separation or using the relevant enantiomer in the synthesis.
• the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
• the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
• the compounds may also exist in one or more crystalline states, i.e. polymorphs, or they may exist as amorphous solids. All such forms are encompassed by the claims.
• the invention also relates to prodrugs of the compounds of the invention.
• prodrugs of the compounds of the invention.
• certain derivatives of compounds of the invention which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
• Such derivatives are referred to as “prodrugs”.
• Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
• This invention also encompasses compounds of the invention containing protective groups.
• compounds of the invention can also be prepared with certain protecting groups that are useful for purification or storage and can be removed before administration to a patient.
• the protection and deprotection of functional groups is described in “Protective Groups in Organic Chemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and “Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).
• the present invention also includes isotopically-labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
• Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
• Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
• isotopically-labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.
• This sulfonyl moiety will always be substituted with a lower alky moiety. Typically it will be methyl.
• the carbon atom adjacent to the sulfonyl may optionally be substituted, as represented by R 2 . Typically both R 1 and R 2 will be methyl.
• the carbon adjacent to the sulfonyl moiety is a chiral center. Therefore the compounds can exist as the racemate, as the S enantiomer, or as the R enantiomer. In a further embodiment, the compounds may be prepared and administered as the R-enantiomer, as depicted below:
• the compound as synthesized will rarely be present exclusively as a single enantiomer.
• the opposite enantiomer i.e the S-enantiomer
• This pyridinone ring will be connected to the rest of the molecule via the 1- and 4-positions as depicted above.
• the pyridinone moiety may be optionally substituted, as depicted by the R 3 moiety.
• R 3 may represent one non-hydrogen substituent, as defined above. This non-hydrogen substituent may be located at any of positions 3, 4 or 5 of the pyridinone ring. Typically R 3 will represent hydrogen.
• D may be any of aryl, cycloalkyl, heteroaryl or heterocyclic, as defined above. These ring systems may also be optionally substituted, as defined above. Any chemically permissible position of D may be bonded to the 4-position of the pyridine ring or D may be connected to the pyridinone via the linker as defined by L.
• the molecule may contain one of the substituents defined by G.
• G if present, may be bonded directly to D.
• the linker T may connect G and D.
• G may be any of aryl, cycloalkyl, heteroaryl or heterocyclic as defined above. These ring systems may also be optionally substituted, as defined above.
• the molecule may terminate with either T or D as the tail. If the molecule terminates with T, then one skilled in the art will recognize that any of the linkers specified above will have an additional hydrogen atom on the terminal atom of that specific substituent, due to the lack of a bond to G.
• the invention is directed to a subgenus represented by formula Ia below.
• L, T and G are all absent.
• D is phenyl optionally substituted, R 3 is hydrogen and the compound is present as the R-enantiomer (i.e. the S-enantiomer may optionally be present as a minor impurity, typically no more than 5 w/w %, more typically no more than 1 w/w %).
• the phenyl ring is substituted with up to 3 substituents selected from the group consisting of halogen, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, trifluoromethyl, trifluoromethoxy, and C 1 -C 3 alkyl, optionally substituted with hydroxy or halogen.
• the invention is directed to a subgenus represented by formula Ib below As depicted, L and T are both absent, D is phenyl bonded directly to G which is optionally substituted heteroaryl.
• R 3 is hydrogen and the compound is present as the R-enantiomer (i.e. the S-enantiomer may optionally be present as a minor impurity, typically no more than 5 w/w %, more typically no more than 1 w/w %).
• the compounds of Formula I can be prepared by a variety of methods that are analogously known in the art.
• the reaction schemes presented below illustrate one method for preparing these compounds. Others, including modifications thereof, will be readily apparent to one skilled in the art.
• Step A illustrates how to prepare the compounds of Formula I.
• the initial step in the synthesis is to conduct an N-alkylation reaction between the pyridinone of structure 1 and the sulfonyl derivative of structure 2, generating the sulfonyl-pyridinone derivative of structure 3.
• Step B which is further illustrated in Scheme B
• the terminal carboxylate of structure 3 is converted to a hydroxamic acid derivative as is depicted in structure 4.
• Step C which is further illustrated in Scheme C, the terminal moiety, L-D-T-G, is attached to the 4-position of the pyridinone moiety, generating the desired compound of Formula I.
• Step B and Step C are carried out is not critical. If desired, the terminal moiety represented by L-D-T-G may be attached to the pyridinone and then the hydroxamic moiety may be incorporated into the molecule. Likewise, the synthetic team may partially complete either Step B or Step C and return to this portion of the molecule after completing the modifications required at the other end of the molecule. Such variations are readily apparent to one of skilled in the art.
• Step A The N-alkylation depicted above in Step A can be carried out using techniques well known to medicinal chemists.
• One of the starting materials is the 2-pyridinone derivative of structure 1.
• R 3 should be represented by the same moiety as is desired in the final product, or a protected variation thereof.
• Many of these pyridinone derivatives are known in the art and the remainder can be produced using synthetic techniques analgously known in the art. The reader's attention is directed to Tet. Lett . (2005) Vol 46, 7917 for a description of such techniques.
• Preparation 2A infra also illustrates their preparation.
• the other reactant is the protected alkyl sulfonate of structure 2.
• R 1 and R 2 should both be represented by the same moiety as is desired in the final product. An ethyl protecting group is depicted, but any standard protecting group may be substituted. These alkyl sulfonates are also known in the art. The reader's attention is directed to JOC , (1980) Vol 45, 8, 1486-89 for a description of their preparation. Preparation 1A infra, also illustrates their preparation.
• the N-alkylation can be carried out as is known in the art.
• equivalent amounts of the compounds of structure 1 and 2 are contacted in an aprotic solvent such as tetrahydrofuran in the presence of a weak base such as potassium carbonate, cesium carbonate, sodium carbonate, etc.
• a weak base such as potassium carbonate, cesium carbonate, sodium carbonate, etc.
• the reactants are typically heated and the reaction is continued until completed.
• the desired product of structure 3 can be recovered and isolated as is known in the art. If desired, it can be purified, or alternatively the crude can be used in the next step of the reaction.
• Scheme B illustrates how to incorporate the hydroxamic acid moiety into the molecules.
• the protecting group is removed from the carboxylic acid, thereby generating the intermediate of structure 3′.
• the manner in which this is accomplished will vary with the identity of the actual protecting group and is well known to those skilled in the art.
• Step 2 the hydroxamic acid moiety, as depicted, is incorporated into the molecule.
• This can also be carried out as is known in the art.
• a protected hydroxylamine may be used, followed by a subsequent deprotection reaction.
• hydroxylamine may be directly incorporated.
• the hydroxamic acid functionality is incorporated into the molecule using standard amidation reactions.
• the compound of structure 3′ may be contacted with an excess of oxalyl chloride, in an aprotic solvent such as dichloromethane to allow formation of the corresponding acid chloride, followed by the addition of an excess of either the hydroxylamine or protected hydroxylamine.
• the reaction is then allowed to proceed to completion and the compound of structure 4 or its corresponding protected intermediate is isolated from the reaction medium and purified as is known in the art.
• any deprotection, if required, may be carried out as is known in the art.
• the amide can be formed using the amide coupling reagent, 1,1′-carbonyliimidazole or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (“EDCI”), as is known in the art.
• the halide function at the 4-position is directly displaced by the desired tail group.
• the halide moiety is converted to a boronate ester which is subsequently displaced by the desired tail group. Either strategy may be utilized.
• the boronation can be carried out using techniques well known to those skilled in the art.
• the intermediate of structure 4 is placed in an aprotic solvent (such as tetrahydrofuran or dioxane) and then contacted with an organobornane (such as neopentyl diboron, bis(pinolacto)diborane, etc.) in the presence of both a transition metal catalyst (i.e. palladium) and a base (potassium acetate, cesium carbonate, etc.).
• a transition metal catalyst i.e. palladium
• a base potassium acetate, cesium carbonate, etc.
• the borylated intermediate describe by structure 4′ may be isolated and purified as is known in the art, or the crude may be used directly in the next step of the reaction.
• a coupling reaction is ultimately carried out to attach the terminal moiety, G-T-D-L, to the 4-position of the pyridinone intermediate.
• the co-reactant is depicted as G-T-D-L-M 1 .
• the co-reactant with the pyridinone may be any of D-M 1 , T-D-M 1 , G-T-D-M 1 , G-T-D-L-M 1 , T-D-L-M 1 or D-L-M 1 .
• G-T-D-L-M 1 will be represented by the same moiety as desired in the final product, except that it will be substituted by a halogen atom, a metal such as magnesium, copper, or a boronate ester, etc. at the desired point of attachment to the pyridinone intermediate (i.e. the other reactant).
• the tails encompassed by Formula I, i.e G-T-D-L, are either known in the art or can be prepared by methods analogously known in the art.
• the manner in which the coupling reaction is carried out varies with the type of bond being formed, i.e. (carbon-carbon, carbon-nitrogen, carbon-oxygen, carbon-sulfur, etc.). If a carbon-carbon bond is desired, then a Suzuki-Miyaura strategy may be used. In such a reaction M 1 will be represented by a boronic acid/ester or a halogen atom.
• Equivalent molar amounts of the reactants will be contacted in a solvent such as THF, dioxane, water, toluene, or an admixture thereof; in the presence of a transition metal catalyst such as palladium, or nickel (or resin bound catalyst) along with a base such as sodium carbonate, potassium carbonate, cesium fluoride or cesium carbonate.
• a transition metal catalyst such as palladium, or nickel (or resin bound catalyst) along with a base such as sodium carbonate, potassium carbonate, cesium fluoride or cesium carbonate.
• the reactants will be heated by microwave or other conventional technique till completed. Once completed the desired product may be isolated and recovered from the reaction and further purified as is known in the art.
• M 1 will be copper or nickel and the 4-position of the pyridinone will be substituted with an iodine atom (i.e. Option A will be chosen).
• Equivalent amounts of the reactants will be contacted in an aprotic solvent such as ether, DMF, or DME and the reactants are heated till the reaction is completed.
• the desired product of formula I may be isolated and purified as is known in the art.
• G-T-D-L-M 1 will be represented by the same moiety as desired in the final product, except that it will be substituted by a hydroxyl function at the desired point of attachment to the pyridinone. If a thioether is desired, G-T-D-L-M 2 will be an appropriately substituted disulfide moiety.
• the Ullmann ether reaction can be carried out in the presence of copper salts. If a Williamson ether approach is used, then equivalent amounts of the reactants will be contacted in an aprotic solvent such as dioxane in the presence or absence of a phase transfer catalyst such as 18-crown-6. A base such as potassium hydroxide, sodium t-butoxide or sodium methoxide will typically be added as well. The reactants will be heated by microwave or other conventional technique to reaction completion. The desired product may be isolated and purified as is known in the art.
• a Buchwald-Hartwig cross-coupling or Ullmann strategy similar to that described above, may be utilized. Equivalent amounts of the reactants will be contacted in an aprotic solvent solvent such as ether, dimethylformamide, or dimethyoxyethane in the presence of a source of copper, such as copper acetate, and a base such as pyridine or catalyst such as a palladium complex. The reaction will be allowed to proceed to completion and the desired product may be isolated and purified as is known in the art.
• an aprotic solvent solvent such as ether, dimethylformamide, or dimethyoxyethane
• a source of copper such as copper acetate
• a base such as pyridine
• catalyst such as a palladium complex
• reaction schemes depicted above for producing the compound of Formula I are merely illustrative. As is readily apparent to one skilled in the art, they may be modified depending upon the specific compound, availability of reagents, etc.
• the compounds may be used for the treatment or prevention of infectious disorders, especially those caused by susceptible and multi-drug resistant (MDR) Gram-negative bacteria.
• Gram-negative bacteria include Acinetobacter baumannii, Acinetobacter spp., Achromobacter spp., Aeromonas spp., Bacteroides fragilis, Bordetella spp., Borrelia spp., Brucella spp., Campylobacter spp., Citrobacter diversus ( koseri ), Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Francisella tularensis, Fusobacterium spp., Haemophilus influenzae ( ⁇ -lactamase positive and negative), Helicobacter pylori, Klebsiella oxytoca, Klebsiella pneumoniae (including those encoding extended-spectrum ⁇ -lactamases (hereinafter “ESBLs
• the Gram-negative bacteria are selected from the group consisting of Acinetobacter baumannii, Acinetobacter spp., Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Serratia marcescens, Pseudomonas aeruginosa and members of the Enterobacteriaceae and Pseudomonas that express ESBLs, KPCs, CTX-M, metallo- ⁇ -lactamases, and AmpC-type beta-lactamases that confer resistance to currently available cephalosporins, cephamycins, carbapenems, and beta-lactam/beta-lactamase inhibitor combinations.
• infections examples include nosocomial pneumonia, urinary tract infections, systemic infections (bacteremia and sepsis), skin and soft tissue infections, surgical infections, intraabdominal infections, lung infections in patients with cystic fibrosis, patients suffering from lung infections, endocarditis, diabetic foot infections, osteomyelitis, and central nervous system infections.
• the compounds can be used to treat Helicobacter pylori infections in the GI tract of humans (and other mammals). Elimination of these bacteria is associated with improved health outcomes including fewer dyspeptic symptoms, reduced peptic ulcer recurrence and rebleeding, reduced risk of gastric cancer, etc.
• H. pylori and its impact on gastrointestinal illness may be found at: www.informahealthcare.com, Expert Opin. Drug Saf. (2008) 7(3).
• the compounds need to be administered in a therapeutically effective amount.
• a “therapeutically effective amount” is meant to describe a sufficient quantity of the compound to treat the infection, at a reasonable benefit/risk ratio applicable to any such medical treatment. It will be understood, however, that the attending physician, within the scope of sound medical judgment, will decide the total daily dosage of the compound.
• the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
• the total daily dose will typically range from about 0.1 mg/kg/day to about 5000 mg/kg/day in single or in divided doses.
• dosages for humans will range from about 10 mg to about 3000 mg per day, in a single or multiple doses.
• Parenteral administrations include injections to generate a systemic effect or injections directly into to the afflicted area. Examples of parenteral administrations are subcutaneous, intravenous, intramuscular, intradermal, intrathecal, and intraocular, intranasal, intravetricular injections or infusions techniques.
• Topical administrations include the treatment of areas readily accessibly by local application, such as, for example, eyes, ears including external and middle ear infections, vaginal, open wound, skin including the surface skin and the underneath dermal structures, or other lower intestinal tract.
• Transmucosal administration includes nasal aerosol or inhalation applications.
• compositions can be formulated for administration by any route known in the art, such as subdermal, by-inhalation, oral, topical or parenteral.
• the compositions may be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
• topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, ophthalmic ointments/drops and otic drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients, etc.
• Such topical formulations may also contain conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present, for example, from about 1% up to about 98% of the formulation.
• Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
• the tablets may be coated according to methods will known in normal pharmaceutical practice.
• Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
• fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being typical.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
• the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
• agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• compositions may contain, for example, from about 0.1% by weight, to about 60% by weight, of the active material, depending on the method of administration.
• each unit will contain, for example, from about 5-500 mg of the active ingredient.
• the dosage as employed for adult human treatment will range, for example, from about 10 to 3000 mg per day, depending on the route and frequency of administration.
• the compounds of the invention may be administered in combination with one or more additional anti-bacterial agents (“the additional active agent”).
• the additional active agent may be for simultaneous, separate or sequential use.
• LRMS Low Resolution Mass Spectra
• LRMS Low Resolution Mass Spectra
• APCI Atmospheric Pressure Chemical Ionization
• reaction conditions length of reaction and temperature
• reaction conditions may vary.
• reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate.
• Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate R f s or retention times.
• Purity of the enantiomers was determined via chiral HPLC, 4.6 ⁇ 250 mm Chiralpak AD, 10 ⁇ column, 215 nm wavelength, mobile phase: ethanol, isocratic elution at 1 mL/min at ambient temperature.
• Benzyl alcohol (242 mL, 253 g, 2.34 mol) and pyridine (204 mL, 204 g, 2.57 mol) were dissolved in methylene chloride (2.5 L) and cooled to 0° C.
• 2-Chloropropanoyl chloride (250 mL, 327 g, 2.57 mol) was added dropwise keeping the temperature between 0° C. and 5° C. After addition the mixture was allowed to warm to RT overnight. The mixture was washed with 20% aqueous citric acid (2.5 L), saturated aqueous NaHCO 3 (2.5 L), brine (2.5 L), dried (MgSO 4 ), filtered and concentrated in vacuo.
• Step D Chiral separation of Benzyl (+/ ⁇ )-4-bromo-2-methyl-2-(methylsulfonyl)butanoate
• Scheme 2 illustrates the preparation of 4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide and its corresponding R-enantiomer.
• the reaction sequence in Preparation 2B is the same with the exception that benzyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate is used as a starting material in order to arrive at the desired enantiomer.
• the resulting mixture was stirred at ambient temperature overnight.
• the mixture was diluted with methylene chloride and water.
• the phases separated and the aqueous extracted with methylene chloride two times.
• the organic extracts were combined and dried over magnesium sulfate, filtered and concentrated to a crude residue.
• the crude residue was dissolved in methylene chloride ( ⁇ 150 mL) with minimal methanol. To this solution was added heptanes (450 mL) and the mixture was concentrated in vacuo to 150 mL and filtered.
• Neopentyl diboron (9.4 g, 28 mmol), KOAc (7.1 g, 69 mmol, 3 eq.) and Pd(dppf)Cl 2 (532 mg, 0.69 mmol, 0.03 eq.) was added into a 200 mL round bottom flask equipped with a magnetic stirrer and a 120 mL addition funnel.
• the product of Step B of Preparation 2B, (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid T5 (9.2 g, 23 mmol, 1.0 equiv.) was added into the addition funnel.
• the system was purged with nitrogen/vacuum and kept under nitrogen.
• Degassed DMSO 45 mL was added into the addition funnel.
• the system was again purged with N 2 for 5 mins.
• the T5 solution was added to the reaction mixture over 2 mins at room temperature then heated to 80° C. and maintained at that temperature for a further hour.
• the reaction mixture was cooled to RT and poured into 100 mL water. Mixture was adjusted to pH 3 with 6 N HCl and refrigerated for 30 min. A dark solid formed and was collected via filtration and dried under high vacuum over P 2 O 5 for 3 days to yield 13 g of solid product.
• the solid was suspended in 100 mL MeOH, 16 g silica gel was added and mixture was concentrated in vacuo.
• the preabsorbed material was packed into a cartridge, loaded onto an 80 g silica gel column and purified using 0 to 20% MeOH in DCM (product eluted out at ⁇ 8% MeOH) in 45 min at 60 mL/min flow rate. The desired fractions were concentrated to furnish 6.3 g off white solid (71%).
• Step B (2R)-2-methyl-2-(methylsulfonyl)-4- ⁇ 2-oxo-4-[4-(1H-pyrazol-1-yl)phenyl]pyridin-1(2H)-yl ⁇ -N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Trisdibenzylidine dipalladium 29 mg, 0.049 mmol was added to a mixture of potassium carbonate (343 mg, 2.46 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H-pyrazole (133 mg, 0.49 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (245 mg, 0.49 mmol), which may be synthesized as described in Preparation 2B in 1,2-dimethoxyethane-methanol (5.0 mL, 1:1).
• Pd EnCatTM (133 mg, 0.04 mmol, 0.1 equiv), was added to a mixture of potassium carbonate (166 mg, 1.2 mmol, 3.0 equiv), [(E)-2-phenylvinyl]boronic acid (65 mg, 0.44 mmol, 1.1 equiv), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (200 mg, 0.40 mmol), which may be synthesized as described Preparation 2B, in 2:1 1,4-dioxane-water (3.6 mL).
• Step B) 2R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4- ⁇ 2-oxo-4-[(E)-2-phenylvinyl]pyridin-1(2H)-yl ⁇ butanamide
• Step C) 4-[4- ⁇ 4-[3-(4,4-difluoropiperidin-1-yl)propoxy]phenyl ⁇ -2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• 1,4-dioxaspiro[4.5]decan-8-ol ref 1 (3.6 g, 20.8 mmol) was added to a solution of 4-bromophenol (3.00 g, 18.96 mmol) in THF (20 mL). Triphenylphosphine (4.96 g, 18.9 mmol) and triethylamine (1.92 g, 18.9 mmol) were added. The resulting solution was cooled to 0° C. and DIAD (3.83 g, 18.9 mmol) was added by dropwise addition. The reaction was maintained at 0° C. for 30 minutes then warmed to room temperature and stirred over night. The reaction was quenched by addition of water and extracted with ether (2 ⁇ 100 mL).
• Step D 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]cyclohexanol
• Pd EnCatTM (344 mg, 0.13 mmol) was added and the resulting suspension was heated to 80° C. After 2 hours the reaction was cooled to room temperature, diluted with ethyl acetate (50 mL) and filtered through celite eluting with ethyl acetate (50 mL). The filtrate was concentrated and the residue was partitioned between dichloromethane and water. The layers were separated and the aqueous layer was extracted with dichloromethane (3 ⁇ ). The organic layers were combined, dried (Na 2 SO 4 ), filtered and concentrated.
• Step B (+/ ⁇ )-[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol and (+/ ⁇ )-[trans-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methanol
• Example 6 The following compounds can be prepared by the procedures described in Example 6 through Example 10 where the appropriate alcohol or protected derivative thereof is employed. Methods used to describe the synthesis of the precursor are analogously known to those skilled in the art.
• (+/ ⁇ )-Ethyl 2-methyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)butanoate was converted to the title product following the general procedure outlined for (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoic acid, Preparation 2B, Step B.
• the title compound was obtained as a white solid (69.83 g, 95.24%).
• Step C Chiral separation to provide (2R)-2-Methyl-2-(methylsulfonyl)-4-(2-oxo-4-phenylpyridin-1(2H)-yl)butanoic acid
• Pd EnCatTM 150 mg, 0.05 mmol was added to a mixture of potassium carbonate (370 mg, 2.7 mmol) the 2-[3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]tetrahydro-2H-pyran (150 mg, 0.45 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2B, Step C, (267 mg, 0.54 mmol) in 1,4-dioxane (3.5 mL, 0.1M) and water (0.5 mL).
• Pd EnCatTM (0.1 eq) was added to a mixture of potassium carbonate (3.0 eq), (2-fluoro-4-methylphenyl)boronic acid (201 mg, 1.3 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2B (1.0 eq) in dioxane:water (0.1M, 5:1 mixture). The reaction mixture was heated overnight at 80° C.
• Pd EnCatTM 200 mg, 0.6 mmol was added to a mixture of potassium carbonate (250 mg, 1.8 mmol), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (130 mg, 0.72 mmol), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2B, Step C, (300 mg, 0.6 mmol) in dioxane:water (5 mL, 5:1 mixture). The reaction mixture was heated overnight at 80° C.
• Pd EnCatTM (93 mg, 0.03 mmol) was added to a mixture of potassium carbonate (115 mg, 0.83 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (86 mg, 0.33 mmol), and (2R)—N-hydroxy-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanamide (115 mg, 0.28 mmol) in dioxane:water (2.5 mL, 5:1 mixture). The reaction mixture was heated overnight at 80° C. The reaction was cooled to ambient temperature, filtered through a nylon filter and concentrated.
• Step A (2R)-4-[4-(2-Fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid
• Step B (2R)-4-[4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• the resulting suspension was shaken at 80° C. for 14 hr. Complete consumption of starting material was confirmed by LCMS, with the major peak confirmed as desired coupling product by ionization.
• the mixture was then diluted with 2 mL dioxane and 350 mg celite was added. The resulting mixture was shaken at room temperature for 15 min and then filtered. To the filtrate was added 0.5 mL 1 N HCl (aq.) and resulting mixture shaken at room temperature for 4 hrs. The reaction mixture was then concentrated in the Genevac.
• Example 23 was carried out using the general methodology described in Example 22. Title compound was made from the corresponding bromide (0.15 mmol): 4-(4-bromophenyl)-2-methylpyrimidine. Product isolated is an off white solid, 21 mg (31%).
• Example 24 was carried out using the general methodology described in Example 22. Title compound was made from the corresponding bromide (0.15 mmol): 5-(4-bromophenyl)-1-methyl-1H-pyrazole. Product isolated is an off white solid, 11 mg (16%).
• Example 25 was carried out using the general methodology described in Example 22. Title compound was made from the corresponding bromide (0.15 mmol): 4-(4-bromophenyl)-2-methyloxazole. Product isolated is an off white solid, 7 mg (10%).
• Example 26 was carried out using the general methodology described in Example 22. Title compound was made from the corresponding bromide (0.15 mmol): 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole Product isolated is a white solid, 14 mg (17%).
• Example 27 was carried out using the general methodology described in Example 22. Title compound was made from the corresponding bromide (0.15 mmol): 5-(4-bromophenyl)-2-methylpyrimidine. Product isolated is an off white solid, 19 mg (28%).
• the reaction was irradiated at 120° C. for 45 minutes in a microwave reactor.
• the reaction was filtered through a thin film of celite, rinsed with ethyl acetate then concentrated. Purification via silica gel chromatography (15% ethyl acetate 85% heptane to 100% ethyl acetate over 45 minutes) and then (5% MeOH 95% ethyl acetate for an additional 5 minutes) afforded the product as a white solid (120 mg, 45%).
• reaction was concentrated then purified via reverse phase chromatography (Method: 95% water/5% methanol (initial conditions) linear gradient to 5% water/95% methanol for 10.0 min, then HOLD 0% water/100% methanol for 1.0 min. Flow rate, 1.5 mL/min Column: Phenomenex Luna (2) C18 4.6 ⁇ 150 mm, 5 um) white solid was isolated (25 mg, 25%)
• the title compound (212 mg, 58%) can be prepared from 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyridine (239 mg, 0.8 mmol) by a procedure analogous to that described for the preparation of (2R)-2-methyl-2-(methylsulfonyl)-4- ⁇ 2-oxo-4-[4-(1H-pyrazol-1-yl)phenyl]pyridin-1(2H)-yl ⁇ -N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step B 4-(4-(4-(3-hydroxypropoxy)phenyl)-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step A 4- ⁇ 4-[4-(3-hydroxypropyl)phenyl]-2-oxopyridin-1(2H)-yl ⁇ -2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step B N-hydroxy-4- ⁇ 4-[4-(3-hydroxypropyl)phenyl]-2-oxopyridin-1(2H)-yl ⁇ -2-methyl-2-(methylsulfonyl)butanamide
• Step B Tert-butyl(diphenyl) ⁇ 2-[3-(tetrahydro-2H-pyran-2-yloxy)cyclobutyl]ethoxy ⁇ silane
• Pd EnCatTM 130 mg, 0.051 mmol was added to a mixture of potassium carbonate (221 mg, 1.60 mmol), 1-benzofuran-2-ylboronic acid (271 mg, 0.954 mmol), and 4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2A (240 mg, 0.63 mmol) in dioxane:water (5 mL, 4:1) in a 2-5 mL microwave vial and the reaction was heated at 90° C. overnight.
• (+/ ⁇ )-4-(4-Iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be produced as in Preparation 2A and (6-methoxy-2-naphthyl)boronic acid were converted to the title product following the general procedure outlined for (+/ ⁇ )-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (Example 33, Step A).
• the title compound was obtained as a white solid (452.7 mg, 85.3%) LC-MS m/z 529.7 (M+1).
• Step B N-hydroxy-4-[4-(6-methoxy-2-naphthyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide
• (+/ ⁇ )-4-[4-(6-Methoxy-2-naphthyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide was converted to the title product following the general procedure outlined for (+/+4-[4-(1-Benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (Example 33, Step B).
• the title compound was obtained as a white solid (101.2 mg, 69.9%) LC-MS m/z 445.3 (M+1).
• (+/ ⁇ )-4-(4-Iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be prepared as in Preparation 2A and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyridine were converted to the title product following the general procedure outlined for (+/ ⁇ )-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide in Example 33, Step A.
• the title compound was obtained as a white solid (161 mg, 61%) LC-MS m/z 526.7 (M+1).
• Step B (+/ ⁇ )—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-pyridin-4-ylphenyl)pyridin-1(2H)-yl]butanamide
• (+/ ⁇ )-2-Methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-pyridin-4-ylphenyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide was converted to the title product following the general procedure outlined for (+/ ⁇ )-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide in Example 33, Step B.
• the title compound was obtained as a white solid (90 mg, 62%) LC-MS m/z 442.3 (M+1).
• Trifluoromethanesulfonic anhydride (1.40 mL, 8.32 mmol) was added dropwise via a syringe to a solution of quinolin-7-ol (930 mg, 6.41 mmol), and pyridine (1.05 mL, 13.0 mmol) in anhydrous dichloromethane (50 mL) at 0° C. After addition the ice bath was removed and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was concentrated and purified via flash chromatography using an Analogix SF25-40 g column and eluant of ethyl acetate in heptane (0-40%) to afford the title compound as an orange-white solid (1.54 g, 86.7%).
• (+/ ⁇ )-4-(4-Iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be produced as in Preparation 2A and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline were converted to the title product following the general procedure outlined for (+/ ⁇ )-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide in Example 33, Step A.
• the title compound was obtained as a white solid (221 mg, 88.1%) LC-MS m/z 500.7 (M+1).
• Step D N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(2-oxo-4-quinolin-7-ylpyridin-1(2H)-yl)butanamide, hydrochloride salt
• Step B 4- ⁇ 2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl ⁇ pyridine
• Potassium acetate (391 mg, 3.98 mmol) was added to a solution of 4-[2-(4-bromophenoxy)ethyl]pyridine (370 mg, 1.33 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (405 mg, 1.60 mmol), and [1,1′-bis-(diphenylphosphino)ferrocene]-dichloropalladium (II) dcm complex (325 mg, 0.40 mmol) in 1,4-dioxane (5.0 mL) in a 20 mL vial. The vial was capped and heated to 80° C.
• (+/ ⁇ )-4-(4-Iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be produced as in Preparation 2A and 4- ⁇ 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl ⁇ pyridine were converted to the title product following the general procedure outlined for (+/ ⁇ )-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide in Example 33, Step A.
• the title compound was obtained as a white solid (44.1 mg, 15.4%) LC-MS m/z 568.8 (M ⁇ 1).
• Step D N-hydroxy-2-methyl-2-(methylsulfonyl)-4- ⁇ 2-oxo-4-[4-(2-pyridin-4-ylethoxy)phenyl]pyridin-1(2H)-yl ⁇ butanamide, hydrochloride salt
• (+/ ⁇ )-2-Methyl-2-(methylsulfonyl)-4- ⁇ 2-oxo-4-[4-(2-pyridin-4-ylethoxy)phenyl]pyridin-1(2H)-yl ⁇ -N-(tetrahydro-2H-pyran-2-yloxy)butanamide was converted to the title compound following the general procedure outlined for (+/ ⁇ )-4-[4-(1-benzofuran-2-yl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide in Example 33, Step B.
• Step B (2R)-2-methyl-4- ⁇ 4-[4-(5-methyl-1,3-oxazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl ⁇ -2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step B (2R)-2-methyl-2-(methylsulfonyl)-4- ⁇ 2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl ⁇ -N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Pd EnCatTM 200 mg, 0.06 mmol was added to a mixture of potassium carbonate (250 mg, 1.81 mmol), (4-fluorophenyl)boronic acid (84 mg, 0.602 mmol), and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, which may be produced as in Preparation 2 B, (300 mg, 0.602 mmol) in dioxane:water (5.5 mL, 10:1 mixture) in a 25 mL round bottom flask.
• the title compound was produced following the general method of Example 41, Step A, using (3-fluorophenyl)boronic acid (84 mg, 0.602 mmol).
• the crude product was purified by chromatography on silica gel (elution solvent: ethyl acetate) to provide title compound as a viscous, foamy oil. Yield: 125 mg, 44.5%.
• Example 41 Title compound was produced by following the general method of Example 41, Step A, using (2-fluorophenyl)boronic acid (84 mg, 0.602 mmol).
• the crude material was purified by chromatography on silica gel (elution solvent: ethyl acetate) to provide title compound as a viscous, foamy oil. Yield: 180 mg, 64.1%.
• Example 41 Title compound was produced by following the general method of Example 41, Step A, using (2,3-difluoro-4-methoxyphenyl)boronic acid (113 mg, 0.602 mmol.
• the resulting crude material was purified by chromatography on silica gel (elution solvent: ethyl acetate) to provide title compound as a viscous, foamy oil. Yield: 132 mg, 42.6%.
• Example 41 Title compound was produced by following the general method of Example 41, Step A, using (3-chloro-2-fluorophenyl)boronic acid (105 mg, 0.602 mmol).
• the crude material was purified by chromatography on silica gel (elution solvent: ethyl acetate) to provide title compound as a viscous, foamy oil. Yield: 137 mg, 45.4%.
• Example 41 Title compound was produced by following the general method of Example 41, Step A, using (2,3-dichlorophenyl)boronic acid (115 mg, 0.602 mmol). The resulting crude material was purified by chromatography on silica gel (elution solvent: ethyl acetate) to provide title compound as a viscous, foamy oil. Yield: 142 mg, 45.6%. MS (APCI (type)) m/z 539.5 (M+Na).
• Step B (2R)-2-methyl-2-(methylsulfonyl)-4- ⁇ 2-oxo-4-[4-(tetrahydro-2H-pyran-4-yl)phenyl]pyridin-1(2H)-yl ⁇ -N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step B) 2R)-4-[4- ⁇ 4-[(2-methoxyethyl)thio]phenyl ⁇ -2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step A 2-(4-chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
• Step B (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid
• Step C (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step D (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
• Step B 4-[4-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl) butanoic acid
• Step C 4-[4-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step D 4-[4-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
• Step B 4-(4-Iodo-3-methyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl) butanoate
• the resulting mixture was stirred at ambient temperature overnight.
• the mixture was diluted with methylene chloride and washed successively with sat. aqeous sodium bicarbonate, aqueous HCl (1N) and water.
• the organic extracts were dried over magnesium sulfate, filtered and concentrated to a crude residue.
• the crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol.
• Step A 4-(4-Cyclohexyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step B 4-(4-Cyclohexyl-2-oxopyridin-1(2H)-yl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
• Pd EnCatTM (172 mg, 0.067 mmol) was added to a mixture of potassium carbonate (298 mg, 2.16 mmol), phenylboronic acid (132 mg, 1.08 mmol), and ethyl (2R)-4-(3-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (288 mg, 0.647 mmol) in 1,4-dioxane:water (10 ml, 4:1) in a 20 ml vial. The vial was sealed and the reaction was heated to 80° C. and allowed to stir overnight at that temperature.
• n-Butyllithium (2.5 M in hexanes, 18.6 mL, 46.5 mmol) was added to a solution of diisopropylamine (6.51 mL, 46.1 mmol) in anhydrous tetrahydrofuran (85 mL) at ⁇ 78° C. and stirred at this temperature for 1 hour.
• a solution of 2,5-difluoropyridine (5.0 g, 43 mmol) in anhydrous THF (12 mL) was added dropwise via cannula and the reaction was stirred at ⁇ 78° C. for 3 hours.
• iodine (12.1 g, 47.8 mmol) in tetrahydrofuran (50 mL) was added dropwise via cannula to the reaction at ⁇ 78° C. and stirred at this temperature for 1 hour after complete addition.
• Water 100 mL was added to the reaction and the temperature was allowed to come to RT.
• the reaction was extracted with diethyl ether (3 ⁇ 100 mL). The combined organics were washed with brine (100 mL), dried (MgSO 4 ), filtered and concentrated.
• Pd EnCatTM (95 mg, 0.037 mmol) was added to a mixture of potassium carbonate (312 mg, 2.26 mmoll), phenylboronic acid (131 mg, 1.07 mmol), and ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (319 mg, 0.716 mmol) in dioxane:water (10 ml, 4:1) in a 20 mL vial equipped with a stir bar. The reaction was heated to 90° C. and allowed to stir overnight at that temperature.
• Step F ((2R)-4-(5-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• the title compound was prepared following analogous procedures described wherein sodium ethyl sulfinate was used instead sodium methyl sulfinate for the preparation of 1A to provide 2-ethanesulfonyl-propionic acid ethyl ester.
• the title compound may then be produced by following the general methodology of Example 11. MS (LCMS) m/z 379.5 (M+1).
• Step E 4-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole
• Pd EnCat (98 mg, 0.03 mmol) was added to a mixture of potassium carbonate (171 mg, 1.24 mmol), 4-methoxy-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H-1,2,3-triazole (138 mg, 0.457 mmol) and (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide which may be produced as in Preparation 2B(T6) (190 mg, 0.381 mmol) in dioxane:water (6 ml, 5:1 mix) in a 20 ml vial.
• Step E (2R)—N-hydroxy-4-[4- ⁇ 4-[(6-methoxypyridin-3-yl)methoxy]phenyl ⁇ -2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide
• the title compound can be made following the procedure described in Eur. J. Org. Chem. 2008, 3479-34871, except that 4-dioxaspiro[4.5]decan-8-one was used as the ketone substrate.
• the resulting product was purified via silica gel chromatography (10% ethyl acetate 90% heptane to 100% ethyl acetate over 45 minutes. Isolated (6000 mg, ⁇ 100%).LCMS 259.2 1 H NMR (400 MHz, CHLOROFORM-d) ⁇ ppm 1.67 (s, 4H) 2.12 (qq, 2H) 2.57-2.63 (m, 4H) 2.83-2.89 (m, 4H) 3.93-3.96 (m, 4H)
• Step B 8((4-bromophenoxy)difluoromethyl)-1,4-dioxaspiro[4.5]decane
• Trifluoromethanesulfonic acid (0.681 mL, 7.82 mmoles) was added dropwise to a stirred solution of 8-[1,3]dithian-2-ylidene-1,4-dioxa-spiro[4,5]decane (2000 mg, 7.740 mmoles) in 25 mL of dichloromethane at ⁇ 22° C.
• the solution was allowed to warm to room temperature and stirred for 30 minutes
• the black reaction mixture was cooled to ⁇ 72° C. and a solution of 4-bromo-phenol (2010 mg, 11.6 mmoles) and triethylamine (1.90 mL, 13.6 mmoles) in 25 mL of dichloromethane was added (solution turned red).
• the crude material was purified via silica gel chromatography and was eluted with 20% ethyl acetate 80% heptane to 100% ethyl acetate for 45 minutes. The isolated product was taken on directly to the next step. (2.811 g, 24.9%).
• Step C 4-[(4-bromo-phenoxy)-difluoro-methyl]-cyclohexanone
• Step E (2R)-4-[4- ⁇ 4-[difluoro(trans-4-hydroxycyclohexyl)methoxy]phenyl ⁇ -2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• the reaction mixture was irradiated at 120° C. for 45 minutes.
• the crude material was filtered through a thin film of celite and was rinsed with ethyl acetate then the filtrate was concentrated in vacuo.
• the material was purified via silica gel chromatography (15% EtOAc 85% heptane to 100% ethyl acetate over 45 minutes and then 5% MeOH 95% ethyl acetate for an additional 5 minutes). Isolated 290 mg title compound (95.6%) LCMS ES-611.8
• Step F (2R)-4-[4- ⁇ 4-[difluoro(trans-4-hydroxycyclohexyl)methoxy]phenyl ⁇ -2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
• Step B) ⁇ 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-piperidin-4-yl ⁇ -methanol
• Step C (R)-4- ⁇ 4-[4-(4-Hydroxymethyl-piperidin-1-yl)-phenyl]-2-oxo-2H-pyridin-1-yl ⁇ -2-methanesulfonyl-2-methyl-N-(tetrahydro-pyran-2-yloxy)-butyramide
• Step D (R)—N-Hydroxy-4- ⁇ 4-[4-(4-hydroxymethyl-piperidin-1-yl)-henyl]-2-oxo-2H-pyridin-1-yl ⁇ -2-methanesulfonyl-2-methyl-butyramide
• Step A 4-[4-(4-Acetylphenyl)-2-oxopyridin-1(2H)-yl]-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide
• Step B N-Hydroxy-4-[4- ⁇ 4-[(1E)-N-methoxyethanimidoyl]phenyl ⁇ -2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide
• Step A 5-(4-bromo-2-methylphenyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]isoxazole
• Step B 5-[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]isoxazole
• Step C (2R)-4-[4- ⁇ 4-[3-(hydroxymethyl)isoxazol-5-yl]-3-methylphenyl ⁇ -2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step D N-Hydroxy-4-[4- ⁇ 4-[3-(hydroxymethyl)isoxazol-5-yl]-3-methylphenyl ⁇ -2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanamide
• Step A 2(R)-2-Methyl-2-(methylsulfonyl)-4-[2-oxo-4-(3-phenylazetidin-1-yl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• Step B (2R)—N-Hydroxy-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(3-phenylazetidin-1-yl)pyridin-1(2H)-yl]butanamide
• Step A (2R)-2-methyl-2-(methylsulfonyl)-4-(2-oxo-4-(phenylethynyl)pyridin-1(2H)-yl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide
• the crude material was purified via silica chromatography, using 50%-100% [ethyl acetate/hexanes] as the gradient elution solvent.
• the target fractions were combined and concentrated in vacuo to afford a viscous, colorless oil that crystallized upon standing. Yield 107 mg, 57%.
• Step B (R)—N-hydroxy-2-methyl-2-(methylsulfonyl)-4-(2-oxo-4-(phenylethynyl) pyridin-1(2H)-yl)butanamide
• Step A ethyl 4-(4-hydroxy-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl) butanoate
• Ethyl 4-[4-(benzyloxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoate (2.4 g, 5.9 mmol) which may be prepared by the same method disclosed in Example 51, step A, was dissolved in ethanol (100 ml) and cooled with a dry ice/acetone bath. To the cooled solution was added Pearlman's catalyst (2.0 g) and cyclohexene (9.0 ml, 88.4 mmol) then heated to 85° C. for 3 hours. The reaction mixture was cooled to RT and filtered through celite (approx 2 inches) to remove catalyst.
• Step B 4-[4-(3-cyclohexyl propoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)butanoic acid
• the reaction mixture was stirred for 72 hours at RT, was then diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate (50 ml). The product was re-extracted with ethyl acetate (100 ml). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in dioxane (6 ml) and ethanol (6 ml). To this was added a 2.0M aqueous solution of LiOH (2.6 ml, 5.3 mmol).
• the reaction mixture was stirred at RT overnight, then was diluted with 30 ml of water and washed with ethyl acetate (2 ⁇ 50 ml) to remove any TPPO.
• the aqueous phase was adjusted to pH-2 with 1N HCl (10 ml) and the product was extracted with ethyl acetate (3 ⁇ 50 ml).
• the organic phases were combined, dried over sodium sulfate, filtered and concentrated to provide the title compound as a white solid (190 mg, 51%).
• Step C 4-[4-(3-cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide

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